This invention relates generally to capillary valves and devices for interconnecting capillary tubes with each other, with microfabricated devices, and macroscale devices.
Capillary tubes are useful in a wide range of microfluidic applications, particularly where volumes on the order of a microliter or smaller are handled. Capillaries are made of glass, metal, silica, or a polymer. The outer diameter of a capillary tube ranges from under 100 to over 750 microns. The diameter of the inner bore ranges from 2 to over 500 microns. With only minimal amounts of chemicals required, systems utilizing capillary tubes are well suited for producing high sample throughput with minimal use of space and materials. In electrophoretic applications, the high surface to volume ratio of capillaries enables the use of high voltages with low joule heating. The use with high voltages results in the ability to electrophoretically separate compounds in capillary tubes at several times the speed and resolution available with traditional slab electrophoretic separation.
Numerous applications have developed to take advantage of the benefits that capillary tubes provide. For example, one use of capillary tubes is in microfluidic devices where capillary tubes are used to transport small amounts of fluid from one location to another. Another application using capillary tubes entails temporarily sealing both ends of a capillary tube to form a nanoscale reaction vessel. Finally, chromatographic devices utilize capillary tubes to provide a separation column for substances. The substances can then be separated based on their physical properties, such as mass, size, or shape. Such applications include gas chromatography and liquid microbore chromatography.
All of these applications require that sections of capillaries be connected to each other. For example, gas chromatography will require an injection port that can introduce a sample into a flow stream. The varied uses of capillary tubes require capillary connectors that are both versatile and resilient. The physical stresses placed on these capillary connectors are most demanding. The connector must be inert to reactive substances that flow through the capillaries, including organic solvents. The connector must remain leak free when used to contain a liquid, gas, or a fluid separation matrix at pressures ranging from 0 to 10,000 PSI.
In high electric voltage applications, the connector must be insulated from these voltages, which can be over 10,000 volts. The connector should add negligible additional volume to the capillary column to avoid degrading separation resolution in electrophoretic applications. In addition, the connector should be able to act as an interface for connecting macroscale devices (such as injectors, fluid reservoirs, or sample depositors) to microscale capillary tubes. Finally, to aid in the simple manipulation of the connector, the connector must be reusable and simple to connect. The varied uses of the connector in a number of applications require that the connector serve several different functions. Primarily the connector must be able to serve as a leak free, high pressure connector for two or more capillary tubes. The connector should provide a number of other functions as well. The connector could serve as a valve, enabling both the ability to close an end of a section of capillary tubing and the ability to route fluid from one capillary tube into a selectable second capillary tube. In addition, it would be useful for the connector to function as a manifold enabling the combination of the flow streams from a plurality of input capillary tubes to channel into a single output capillary tube or splitting a flow stream from a single capillary tube into multiple flow streams in multiple capillary tubes. The connector preferably would have negligible dead space volume, both as a connector and as a valve. Finally, the connector should enable connection of macroscale devices to microscale capillary tubes.
By combining these features within one connector, a multitude of uses become a possible. By using two such connectors at the two ends of a section of capillary tubes, a reversibly sealable nanoscale reaction chamber is formed. If the first connector also functions as a manifold, a plurality of input lines could flow into this nanoscale reaction chamber before it is sealed to allow for mixing a number of chemicals in the reaction. If the output line also functions as a manifold, once the reaction is complete, the mixture could be divided into multiple lines for sending flow streams to multiple analytical devices or to a waste reservoir.
In the past, several couplers have been developed to attach together the ends of capillary tubes. Some capillary connectors employ a ferrule with a longitudinal bore therethrough for inserting the ends of the capillaries to be coupled together and a compression fitting for mechanically compressing the ferrule to seal the connector. U.S. Pat. No. 5,288,113 to P. H. Silvis et al. teaches a heat-resistant connector for releasably joining end portions of two capillary tubes in end-to-end fashion for use in chromatography. U.S. Pat. No. 5,540,464 issued to Picha, describes a capillary connector where the ends of a capillary tube are press fit into a resilient member with a tapering throughbore. A split sleeve holds a pair of these members together in mutually facing alignment, with the throughbore aligned to enable two capillary tubes to come into fluid communication. U.S. Pat. No. 5,453,170 to S. Krstanovic et al. teaches coupling a capillary to a fine wire electrode to form an ion detector.
Some of the capillary connectors demonstrate the ability to couple together more than two capillaries. U.S. Pat. No. 5,487,569, issued to Silvis et al., teaches a glass insert with a plurality of legs connected at a central portion. Each leg has a tapered inner bore that receives one end of a capillary tube. On each of these legs is annularly mounted a connecting member containing a sealing ferrule for making a seal between the capillary and the leg. U.S. Pat. No. 5,494,641, issued to Krstanovic, describes a system for connecting any number of capillary tubes into a system by mounting the capillary tube within a cavity in a mechanical fastener. The capillary tube can then be attached to any apparatus that has been adapted to accept the fastener.
These capillary connectors function to link sections of capillary tubes. It would be advantageous to have a connector that could serve other functions.
Currently, there are several devices that have been used as valves or gates for capillaries. One capillary valve requires that the capillary tubes be attached to holes in a thin wafer, such as a silicon wafer. A flexible membrane is positioned on the opposite side of the wafer. By exerting pressure on the membrane, the membrane is pressed against the holes in the silicon wafer and the valve is closed. U.S. Pat. No. 5,492,555, issued to Strunk et al., describes a two dimensional capillary gas interface. One part of the device is a bimodal six way capillary valve. This valve comprises a cylindrical section with a longitudinal axis perpendicular to the plane containing the longitudinal axis of three sections of capillary tubes. The valve operates by rotation of the cylindrical section to align the ends of the capillary tube in the tangential plane of the cylinder with the ends of other capillary tubes bringing the section into fluid communication. Further rotation will bring the ends of the capillary tubes in the rotating cylindrical section out of communication with the capillary tubes, closing the valve. This valve has significant dead volume of several microliters.
The inner diameters of capillary tubes must connect to devices that are an order of magnitude or more larger. This has been a persistent problem for the field of microfluidics. Some attempts have been made to provide for a macroscale to microscale interface. For example, capillary tubes have been attached to pressurized reservoirs. An inlet to the reservoir is capped by a rubber septum. A macroscale injector, such as a syringe, can introduce a sample into the reservoir, and the sample will be pressure driven into the capillary tube. After repeated injections through the septum, the septum will no longer remain pressure tight and will require replacement.
Both the connectors and the valves presently available are not ideal. None of these devices combine in one connector the ability to connect a number of capillaries, but also to act as a zero dead volume valve, or as a manifold, or as a router of fluid. As noted above, such a connector would greatly enhance the utility of many systems that use capillary tubes. Furthermore, no device presently available is an adequate interface between macroscale and microscale devices. An object of the invention was to provide improved connectors and valves for capillaries and to connect macroscale devices with macroscale devices.
The above object has been achieved with a capillary connector, which is able to join into fluid communication a plurality of capillary tubes, but also can function as a valve, a fluid router, a manifold, a reaction chamber and a macroscale to microscale connector. Each connector is simple in design and is rapidly and easily connected and disconnected. The connector has negligible dead volume whether functioning as a capillary tube connector, a valve, a fluid rotor, a manifold, a reaction chamber or a macroscale-to-microscale connector. The basic connector consists of two members, with each member consisting of the same basic parts. Each member includes an input bundle of fibers, which are usually capillaries, entering the member, with the input bundle terminating in a ferrule rotatably attached to the member. The input bundle is a set of one or more axially parallel, packed cylinders or fibers, at least one of which is usually a capillary tube, but which also can include non-hollow fibers, such as plugged capillaries, electrodes and fiber optical fibers. The fibers terminate at the end of the ferrule. A fastener connects these two members and holds the ends of the ferrules in mutually biased axially parallel alignment. The rotatable ferrules can then be rotated in relation to each other. The fibers packed within the ferrule would be affixed within the bundle and ferrule and be relatively non-rotating in relation to the bundle and ferrule. By rotation of the ferrules, the rotational orientation of the fibers about an axis in the first bundle would be altered in relation to the orientation of fibers about the same axis in the second bundle, but the axially parallel alignment would remain.
Each member of the connector could have an indicator to indicate the rotational orientation of each ferrule. In one embodiment, the indicators consist of a mark or notch on the ferrule above the centered location of a capillary tube. Alignment of the marks on the two ferrules would indicate that corresponding capillary tubes within the ferrules were aligned and in fluid communication. In another embodiment, optical fibers are used to align the rotation of the capillary connector.
With this basic connector, several different functions are possible. The connector can function to put two corresponding capillary tubes into fluid alignment and thus function as a basic connector. Unlike other available connectors, this connector would also function as a connector between macroscale devices and microscale capillary tubes. It can also function to connect multiple capillaries in one member to a second member with either an equal number of capillaries or with an unequal number of capillaries or only a single capillary.
In addition, the connector can function as a valve. When the ends of the capillaries in both ferrules are aligned, the valve is open. If the ferrule of the second member is rotated in relation to the orientation of the first ferrule, the ends of the capillary tubes can be displaced in relation to each other so that non-corresponding solid cylinders, which may be glass fibers, metal, plastic or a plugged capillary, are aligned with the capillaries and the ends of the capillary tubes will be blocked or closed. These cylinders are generally referred to as non-hollow fibers and plugged capillaries, since these are preferred elements, the main consideration being an outer diameter which is the same as a corresponding capillary which it faces at a ferrule-to-ferrule interface. In other words, when non-hollow fibers are contained within the ferrule of a first connector member, the flow within a capillary could be blocked by orienting the ferrule of a second connector member such that the end of the capillary of the second connector member and the end of the non-hollow fiber of the first connector member are in alignment. The valve is also closed whenever the ends of the capillaries are not aligned with capillaries on the opposing member, including when the ends are aligned with the inter-capillary surfaces. This valve that is created has essentially no dead volume and is simple to manipulate by rotation. The alignment marks, fibers, or scale or notches on the ferrules would indicate if the valve is open or closed. A calibrated scale will allow partial blockage of a capillary by incomplete overlap with the open end of a capillary. If the non-hollow fibers are fiberoptic fibers, alignment could be indicated by passing light through the fibers and detecting if the light passes through a distal end of the fiber. This rotatable valve can also function as a router. For example, if capillaries aligned on ferrules of both members are rotated such that capillaries on a first member now align with different capillaries on the second member, a router is created. Similarly, depending on the application, some capillaries on the first member can be routed to capillaries on the second member, while other capillaries are closed.
Typically, rotation of the ferrule is effected by manual operation. It is also possible to operatively associate the ferrule with a motor to effect automated controlled rotation of the ferrule. The motor would operate in accordance with instructions from a controller that a user would program to give desired results. The orientation of the ferrules would then be automatically controlled with precision timing for volumetric accuracy, especially if variable blockage of a capillary is implemented.
The basic connector, comprised of the two connector members mutually biased against each other, readily transforms into a manifold. This would require that one of the ferrules be associated with a bundle of packed capillary tubes and the second ferrule be associated with a bundle containing one capillary tube. Between these two ferrules would be placed a washer with a cut out pattern. The cut out pattern would bring into fluid communication the flow streams of the plurality of tubes in the first ferrule with the inner bore of the single capillary in the second ferrule. The same result could also be achieved by slightly recessing the capillary tube in one ferrule and having a groove extend between the recessed capillary tubes. This would allow the inner bore of the capillary tube in the second ferrule to come into fluid communication with the first set of capillary tubes. Alternatively, a plurality of capillary tubes in one bundle and ferrule can be associated with a single capillary tube in another bundle and ferrule whereby the inside diameter of the single capillary is large enough to encompass more than one capillary tube in the other ferrule.
This basic connector is adaptable for many different uses. By placing oppositely charged electrical leads on the opposite sides of connector members and filling the tubes with a conducting media, the media will conduct electricity without shorting on the connectors. This enables capillary electrophoresis reactions, electroosmotic pumping or other applications of electrical forces to be performed in the tubes joined by these connectors.
In addition to the use of the present invention wherein two connector members are joined together, the invention also can be used as a single connector member that could be joined to any other device that contains a port member to receive the connector member. This connector member would be comprised of a rotatable ferrule containing at least one capillary tube terminating at a substantially level surface. An alignment indicator on the ferrule, such as a mark or notch, would indicate the orientation of the capillary tubes within the ferrule. The member would have an attachment device, such as an annular nut, capable of attaching to a mating mount, such as a threaded protrusion of a receiving well. This would allow a capillary to be joined to any of a variety of port members, including microfluidic attachments to microchips or attachment to a port member of a moveable arm for the deposition of an array of spots on a surface. The moveable arm would allow placement of such spots in different locations. By including multiple capillary tubes within the ferrule, the connector member could mix compounds on a spot or could be attached to a receptacle for deposition of the reactants to be mixed.